Method for the production of thiazolidin

ABSTRACT

The invention relates to a simple and industrially readily executable method of producing thiazolidine base and salts thereof. In particular, the invention relates to a process for the production of thiazolidine base and salts thereof which is characterized in that hexamethylenetetramine of formula (I)  
                 
 
     is caused to react with cysteamine or salts thereof of formula (II)  
                 
 
     in which X(−) represents an acid residue, X(−) being preferably a halide or sulfate.

CROSS REFERENCE TO OTHER APPLICATIONS

[0001] The present application is claiming priority of DE 19926233.0filed on Jun. 10, 1999 and subsequent PCT EP 00/03213 application filedon, Apr. 11, 2000.

FIELD OF THE INVENTION

[0002] The invention relates to a simple and industrially readilyexecutable method of producing thiazolidine base and salts thereof.

BACKGROUND OF INVENTION

[0003] Thiazolidine can serve as an intermediate for the synthesis ofaminoacyl and peptidyl thiazolidides, which have both a diagnostic and atherapeutic value as enzyme inhibitors [H.-U. DEMUTH, J. EnzymeInhibition 3, 249 (1990)].

[0004] Since aminoacyl thiozolidides are suitable, inter alia, for theregulation of the blood sugar level in mammals, the preparation of thesecompounds and their parent materials using a cost-effective,commercially applicable process is of medical, pharmaceutical andeconomical interest [cƒ DE 19,616,486].

[0005] It is known that thiazolidine and thiazolidine derivatives can beobtained by refluxing aldehydes with aminoethyl sulfate or aminoethylhalides and sodium sulfide in aqueous solution under excess energy inputover a period of several hours. The yields are ca 60% of theory [cƒ U.S.Pat. No. 4,584,407].

[0006] It is an object of the present invention, however, to provide aprocess for the production of thiazolidine base or the salts thereof inwhich no excess energy input is necessary.

SUMMARY OF THE INVENTION

[0007] The present invention now provides a process for the productionof thiazolidine base and salts thereof which is characterized in thathexamethylenetetramine of formula (I) as shown in FIG. 1

[0008] is caused to react with cyst amine or salts thereof of formula(II) as shown in FIG. 2.

[0009] in which X(−) denotes an acid residue, X(−) being preferably ahalide or sulfate.

[0010] It is extremely surprising to find that this process gives thefree base thiazolidine and salts thereof in high yields of very puresubstance without it being necessary to apply excess quantities of heatduring the reaction. This constitutes a cost-effective and technologicaladvantage of the process of the invention particularly as regards theindustrial production of thiazolidine [cƒ EP 0,054,409].

DETAILED DESCRIPTION

[0011] In the present invention, the reaction can take place, eg, in apolar solvent such as an alcohol. Preferred solvents are methanol and/orethanol.

[0012] Another economical and technological advantage of the process ofthe invention for the industrial production of thiazolidine is the factthat hexamethylenetetramine is acceptable as regards the pharmaceuticaluse of the secondary products of thiazotidine, since it ispharmaceutically acceptable: for many years it has been used as a urinedisinfectant and for food preservation [cƒ Mutschler,Arzneimittelwirkungen, pp. 572 et seq., Stuttgart: WissenschaftlicheVerlagsgs. (1986)].

[0013] Preferably, ammonia is used as the initial batch and/or is addedduring the reaction. By this means, synthesis can be carried to thestage of the free base in a single step [cƒ S. Ratner, H. T. Clarke, J.Am. Chem. Soc. 59, pp 200-206 (1937)] so that additional complicated andexpensive reaction stages can be omitted.

[0014] The process of the invention, which is designed for bothlaboratory-scale and commercial-scale applications, is carried out, forexample, by adding hexamethylenetetramine to a preferably methanolicsolution of a cysteamine salt all at once or in a number of portions, assolid matter or dissolved in a solvent. The mixture can be stirred forseveral hours at room temperature, or it may be stirred at temperaturesaround 30-35° C. The stated dosing procedure can take place in reverseorder if desired.

[0015] The process of the invention must not necessarily be carried outunder a blanket of inert gas as in other processes [cƒ EP 0,695,744].

[0016] The thiazolidine produced by the process of the invention can beused as starting material for the production of pharmaceutically usefulactive substances. The invention is illustrated with reference to thefollowing example.

EXAMPLE

[0017] To a solution of 1.358 kg (12 mol) of cysteamine hydrochloride,used as initial batch in 1.8 L of methanol at from 30° to 35° C., thereare added 291.59 g (2.08 mol) of cystamine in two portions at a reactiontemperature of from 30° to 35° C. Following the addition of the firstportion of the hexamethylenetetramine there is observed a distinctexothermal reaction (ca 45° C.) with violet coloration, and the reactionmixture is cooled. Coarse precipitation of ammonium chloride commences.When the exothermal reaction has subsided (after a period of 1.5 h) thesecond portion of hexamethylenetetramine is added. Ammonia is fed to thebatch to saturation, and 700 mL of tertbutylmethyl ether are added.

[0018] The quantitative precipitation of ammonium chloride can beregarded as a process monitor. NH₄Cl is filtered off in vacuo and thefilter cake is washed with the reaction solution. 300 mL ofaminoethylethanolamine are placed in the solution to form a sump.Thiazolidine is purified by distillation, bp: 60-70° C., 8-10 mbar. Theextremely pure substance can be obtain in a yield of 88-93%.

[0019]¹H NMR (200 MHz, D₂O) δ (ppm)=2, 80-2, 83 (t, 3J=6.45 Hz, 2 h, NCH₂CH₂), 3, 04-3, 19 (t, 3J=6.45 Hz, 2 h, CH₂CH ₂S), 4.05 (s, 2 h, NCH ₂S

[0020]¹³C NMR (100.5 MHz, DMSO-d₆) δ (ppm) 30.69 (s, NCH₂CH₂) 47.31 (s,CH₂ CH₂S), 47.95 (s, NCH₂S)

[0021] MS (MALDI-TOF) 89 (M+H) EA: C3H7NS theory: C = 40.44% found: C =40.27% H = 7.91% H = 8.02% N = 15.72% N = 15.90% S = 35.91% S = 35.73%

In the claims: What is claimed:
 1. A process for the production ofthiazolidine base and salts thereof, wherein hexamethylenetetramine offormula (I)

is caused to react with cysteamine or salts thereof of formula (II)

in which X⁽⁻⁾ represents an acid residue.
 2. A process as defined inclaim 1, wherein X⁽⁻⁾ is a halide or sulfate.
 3. A process as defined inclaim 1, wherein the reaction is carried out in a polar solvent.
 4. Aprocess as defined in claim 3, wherein the solvent is an alcohol.
 5. Aprocess as defined in claim 3, wherein the solvent is methanol orethanol.
 6. A process as defined in claim 3, wherein ammonia is addedbefore the reaction.
 7. A process as defined in claim 6, whereinammonium salt is separated.
 8. A process as defined in claim 8, whereinammonium salt is separated.
 9. A process as defined in claim 6, whereinammonium salt is separated and the product is distilled.
 10. A processas defined in claim 8, wherein ammonium salt is separated and theproduct is distilled
 11. A process as defined in claim 2, wherein thereaction is carried out in a polar solvent.
 12. A process as defined inclaim 3, wherein ammonia is added during the reaction.